New organic sulfur compounds and methods for their production

ABSTRACT

1-Carboxyalkyl esters of 5-chlorodithio-2-pyridinecarbamic acid; and salts and lower alkyl esters of those 1-carboxyalkyl esters. The compounds are antiparasitic agents having nematocidal activity and antifungal activity against various species. They can be produced by reacting a tertiary amine salt of 5chlorodithio-2-pyridinecarbamic acid with a haloalkanoic acid salt or haloalkanoic acid ester. The tertiary amine salts of 5chlorodithio-2-pyridinecarbamic acid can be produced by reacting 2-amino-5-chloropyridine with carbon disulfide and a tertiary amine.

United States Patent 1191 Capps et al.

m1 3,725,422 51 Apr. 3, 1973 [54] NEW ORGANIC SULFUR COMPOUNDS ANDMETHODS FOR THEIR PRODUCTION [75] Inventors: David B. Capps, Ann Arbor,Mich.;

Alexander Erdelyi, Vaucluse, Ne

South Wales, Australia I [73] Assignee: Parke, Davis Ir Company Detroit,

Mich.

I [22] Filed: Sept. 7, 1971 211 Appl. Nos 178,469

[52] US. Cl. ..260/294.8 E, 260/270 R, 424/266 {51] Int. Cl. ..C07d31/50 [58] Field of Search ..260/294.8 E, 270 R [56] References CitedUNITED STATES PATENTS 1/1969 Hyatt ..260/294.8 E

Primary Examiner-Alan L. Rotman Attorney-Robert R. Adams et al.

[57] ABSTRACT 9 Claims, No Drawings NEW ORGANIC SULFUR COMPOUNDS ANDMETHODS FOR THEIR PRODUCTION SUMMARY AND DETAILED DESCRIPTION in which Rrepresents hydrogen or lower alkyl, and R represents hydrogen, asalt-forming cation, or lower alkyl. When R or R' represents loweralkyl, it is preferably an alkyl group of not morethan 6 carbon atoms.Some examples of salt-forming cations are pharmaceutically-acceptablealkali metal, alkaline earth metal, aluminum, ammonium, and substitutedammonium cations.

in accordance with the invention, the compounds off the foregoingformula can be produced. by reacting a tertiary amine salt of-chlorodithio-Z-pyridinecarbamic acid having the formula 8 N INH4l-SH-tertiary amine with a haloalkanoic acid saltor haloalkanoic acidester of the formula where R is as defined before, R" represents a saltform'- ing cation (preferably an alkalirnetal cation) or lower alkyl,and Hal represents halogen, preferably chlorine or bromine. Thevhaloalkanoic acid reactant can optionally be employed in the form ofthefree carboxylic acid with an equivalent of a base such as an alkalimetal hydroxide,'an alkaliimetal carbonate, an alkali metal alkoxide, ora tertiary amine, in which case the reactant present in the mixture isthe haloalkanoic acidsalt in which R" representsa salt-formingcation.'lnthe tertiary amine salt of 5-chloridithio-2-pyridinecarbamic acid, thetertiary amine selected is preferably one hav- When R represents loweralkyl, a preferred solvent is ethanol. The reactants can be employed inapproximately equimolar quantities or, if desired, a moderate excess ofeither can be used.'The time and temperature of the reaction are notparticularly critical. in general,

the reaction can be carried out at a temperature from about 0 to C. orthe reflux temperature of the solvent for from 15 minutes to 24 hours,with the longer times being used at the lower temperatures. Preferredconditions are from 20 to 50 C. for a reaction time of 45 minutes to 4hours. When R" represents lower alkyl, the product is isolated directlyas the 5- chlorodithio-2-pyridinecarbamic acid, l-carboxyalkyl I ester,lower alkyl ester. When R" represents a saltforming cation, the productis isolated directly as the 5- chlorodithio-Z-pyridinecarbamic acid,l-carboxyalkyl ester, carboxylate'salt, or, following acidification, asthe 5-chlorodithiO-Z-pyridinecarbamic acid, l-carboxyalkyl ester, freeacidform. The products in which R represents lower alkyl can also beobtained in either racemic, or, byresolution, optically-active dand 1-forms.

Tertiary amine salts of 5-chlorodithio-Z-pyridinecarbarnic acid,required as starting materials in the foregoing process, can be preparedby reacting 2-amino- Schloropyridine with carbon disulfide and atertiary amine in'a solvent such as pyridine.

The free carboxylic acids of the invention form carboxylate salts withany of a variety of inorganic and organic bases.Pharmaceutically-acceptable salts are formed with such bases as sodiumhydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,potassium bicarbonate, ammonia, diethylamine, 2- hydroxyethylamine, andcholine. Pharmaceutically-acceptable magnesium and aluminum salts areformed by reacting the sodium slat or other soluble carboxylate saltswith magnesium chloride or aluminum chloride in aqueous medium. Thepreferred carboxylate salts of the invention are thepharmaceutically-acceptable salts of an alkali metal, an alkaline earthmetal, aluminum, ammonia, or a substituted ammonia. The carboxylic acidsand their salts are interconvertible by adjustment of the pH. Theydiffer in solubility properties but are otherwise equivalent for thepurposes of the invention.

The compounds of the invention can exist in anhydrous form as well as insolvated, including hydrated, forms. In general, the hydrated forms} andthe solvated forms with phannaceutically-accepta'ble solvents areequivalent to theanhydrous or unsolvated form for the purposes of theinvention. I I

v The compounds of the invention are new chemical compounds of value aspharmacological agents and as chemical intermediates. They areantiparasitic agents and especially nematocidal and antifungal agents.Their activity as nematocidal agents can be demonstrated against theparasite Nematospiroides dubius in mice. Mice infected with thisintestinal parasite are given a test compound by gavage.Theselecteddose-is divided into two portionsand both portions are giventhesame day. The efiectivenessof the test compound is :expressed as anapproximate mean effective dose, 1 ED which is the dose that reduces theworm burden in treated animals by 50 percent. The following ED valueswere found for representative compounds of the invention.S-Chlorodithio-Z-pyridinecarbamic acid, 1-

carboxyethyl ester, 8 mg./kg.; -chlorodithio-2- pyridinecarbamic acid,l-carboxypropyl ester, 4 mg./kg.; 5-chlorodithio-2-pyridinecarbamicacid, car boxylmethyl ester, methyl ester, 8 mg./kg.; 5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, isopropylester, 4 mg./kg. The compounds of the invention are active againsthookworms (Ancylostoma caninum) and ascarids (Toxocara canis) in dogs,

v generally in single oral doses of 25 mg./kg. or less. In

EXAMPLE 1 A reaction mixture is prepared by adding 140.4 g. of5-chlorodithio-2-pyridinecarbamic acid, salt with one formula weighttriethylamine, to a solution of 53.6 g. of sodium chloroacetate in 1.3liters of water and 1.6 liters of ethanol. The mixture is heated to 40C. and then allowed to stand at room temperature for 16 hours, dilutedwith 2 liters of water, and acidified with acetic acid. The insolubleproduct is collected on a filter, washed with water, and dried. It is 5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester; m.p. l42 143C., after crystallization from acetonitrile.

The sodium salt is obtained by adding 10 ml. of l N aqueous sodiumhydroxide to a solution of 2.63 g. of the free acid described above in50 ml. of ethanol and evaporating the resulting solution under reducedpressure.

The choline salt is obtained by adding a solution of 1.4 g. of cholinechloride in 10 ml. of methanol to a solution of 2.85 g. of the: sodiumsalt (as prepared above) in 50 ml. of methanol. The mixture is stirredfor one hour and filtered to remove sodium chloride. The filtrate isevaporated under reduced pressure to give the choline salt.

The starting material can be obtained as follows. Carbon disulfide, 55ml., is added to a solution of 100 g. of 2-amino-5-chloropyn'dine and107 ml. of triethylamine in 250 ml. of pyridine. The mixture is allowedto stand at room temperature for 60 hours. The insoluble product whichseparates is collected on a filter and dried. It is5-chlorodithio-Z-pyridinecarbamic acid, salt with one formula weighttriethylamine; m.p. 1l3-114 C. with decomposition. By the substitutionof 145 ml. of tripropylamine for the triethylamine in the foregoingprocedure, the product obtained is 5- chlorodithio-Z-pyridinecarbamicacid, salt with one formula weight tn'propylamine.

EXAMPLE 2 With stirring at 5 C., a suspension of 61.2 g. of 5-chlorodithio-2-pyridinecarbamic acid, salt with one formula weighttriethylamine, in 500 ml. of water is added to a solution of 30.6 g. ofa-bromopropionic acid and 8.0 g. of sodium hydroxide in 500 ml. of 95percent ethanol. The mixture is stirred and warmed to C. over a periodof one hour, held at that temperature for an additional 2.5 hours,cooled to 20 C., and filtered. The filtrate is acidified with aceticacid and diluted with 250 ml. of water. The insoluble product iscollected on a filter, washed with water, and dried. It is 5-chlorodithio-2-pyridinecarbamic acid,. l-carboxyethyl ester; m.p. 136l37 C. with decomposition.

EXAMPLE 3 A suspension of 27.4 g. of 5-chlorodithio-2- pyridinecarbamicacid, salt with one formula weight triethylamine, in 200 ml. of water isadded to a solution of 9.6 g. of a-bromobutyric acid and 3.6 g. ofsodium hydroxide in 24 ml. of water. The mixture is stirred and heatedat 40 C. for 2 hours, cooled to 20 C., and filtered. The filtrate isextracted with dichloromethane and the dichloromethane extract isextracted with 200 ml. of l N aqueous sodium carbonate. The aqueousphases are combined and acidified with hydrochloric acid and extractedwith dichloromethane. This dichloromethane extract is evaporated underreduced pressure to give a residue of 5-chlorodithio-2- pyridinecarbamicacid, l-carboxypropyl ester; m.p. 125127 C. with decomposition, aftercrystallization from acetonitn'le.

EXAMPLE 4 With vigorous stirring, 9.3 ml. of methyl chloroacetate isadded over a 10-minute period to a suspension of 30.0 g. of5-chlorodithio-2-pyridinecarbamic acid, salt with one formula weighttriethylamine, in 180 ml. of 95 percent ethanol. The resulting mixtureis stirred 1.5 hours at room temperature and then diluted with an equalvolume of cold water. The insoluble product is collected on a filter. Itis 5-chlorodithio. 2-pyridinecarbamic acid, carboxymethyl ester, methylester; m.p. l27-128 C. after crystallizations from ethanol.

EXAMPLE 5 EXAMPLE 6 A mixture of 15.3 g. of5-chlorodithio-2-pyridinecarbamic acid, salt with one formula weighttriethylamine, 7.5 g. of propyl chloroacetate, and ml. of ethanol isstirred and heated to 45 C. Stirring is continued an additional 1.5hours while the mixture is allowed to cool.

It is then diluted with 125 ml. of water and chilled to O-5 C. Theinsoluble product is collected on a filter. It is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, propylester; m.p. 9697 C. after crystallization from 95 percent ethanol.

By the foregoing procedure, with the substitution of 8.3 g. of butylchloroacetate for the propyl chloroacetate, the product is5-chlorodithio-2- pyridinecarbamic acid, carboxymethyl ester, butylester; m.p. 9l92 C. after crystallization from ethanol.

By the foregoing procedure, with the substitution of 8.3 g. of isobutylchloroacetate for the propyl chloroacetate, the product is5-chlorodithio-2- pyridinecarbamic acid, carboxymethyl ester, isobutylester; m.p. 9899 C. after crystallizations from ethanol.

By the foregoing procedure, with the substitution 7.5 g. of isopropylchloroacetate for the propyl chloroacetate, the product is5-chlorodithio-2- pyridinecarbamic acid, carboxymethyl ester, isopropylester; m.p. l32-l33.5 C. after crystallization from ethanol.

EXAMPLE 7 A mixture of 15.0 g. of 5-chlorodithio-2-pyridinecarbamicacid, salt with one formula weight triethylamine, 10.0 g. of tert-butylbromoacetate, and 70 ml. of ethanol is stirred and heated to 45 C.Stirring is continued an additional 45 minutes while the mixture isallowed to cool. It is then diluted with 125 ml. of water and chilled to5 C. The insoluble product is collected on a filter. It is-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, tert-butylester; m.p. l4 1l42.5 C. after crystallization from ethanol. The sameproduct is obtained by the substitution of 1.7.0 g. of5-chlorodithio-2-pyridinecarbamic acid, salt with one formula weighttripropylamine, in the foregoing procedure.

We claim:

1. A compound of the formula where R is a member of the class consistingof hydrogen and lower alkyl, and R is a member of the class consistingof hydrogen, pharmaceutically acceptable salt-forming cations, and loweralkyl.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according to claim 2 which is 5-chlorodithio-Z-pyridinecarbamic acid l -carboX- ypropyl ester.

4. A compound according to claim 1 wherein R is lower alkyl.

5. A compound according to claim 4 which is 5-chlorodithio-Z-pyridinecarbamic acid, carboxymethyl ester, methyl ester.

6. A compound according to claim 4 which is 5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, ethyl ester.

compound according to claim 4 which is 5-

2. A compound according to claim 1 wherein R'' is hydrogen.
 3. Acompound according to claim 2 which is 5-chlorodithio-2-pyridinecarbamicacid, 1-carboxypropyl ester.
 4. A compound according to claim 1 whereinR'' is lower alkyl.
 5. A compound according to claim 4 which is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, methylester.
 6. A compound according to claim 4 which is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, ethylester.
 7. A compound according to claim 4 which is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, butylester.
 8. A compound according to claim 4 which is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, isopropylester.
 9. A compound according to claim 4 which is5-chlorodithio-2-pyridinecarbamic acid, carboxymethyl ester, propylester.